Collaboration Reveals Mechanism Central to Iron Homeostasis, Potential Key to Treatment for Iron Overload in Sickle Cell and Thalassemia Patients

Results Provide Fundamental Knowledge for Protein/mRNA Interactions and Illuminate Potential New Treatment Approach for Dangerous Iron Overload in Blood Transfusion PatientsNewswise — May 14, 2012 – Oakland, CA – A landmark study conducted by Children’s Hospital Oakland Research Institute (CHORI) Senior Scientist Elizabeth Theil, PhD, and collaborators at Hunter College/ Graduate Center City University of New York and Case Western Reserve University, demonstrates for the first time that ferrous iron (Fe2+) binds directly to a ribonucleic (RNA) complex to result in a conformational change that ultimately increases iron synthesis. This discovery has profound implications on the fundamental understanding of how Fe2+ and other metal ions interact with RNA, but also provides a potential model for treating dangerous and life-threatening iron overload and for targeting viruses that use similar mechanisms to bind to RNA.

The study was published in an online Early Edition of the Proceedings of the National Academy of Sciences (PNAS) the week of May 14, 2012.

“We have known for a long time that if you give iron to a cell, or to a person for that matter, it increases the synthesis of ferritin, the nano-protein molecule responsible for both storing and releasing iron in the body,” said Dr. Theil. “Now we know how that happens. The results of our study clearly illustrate for the first time the basic genetic mechanism behind iron homeostasis, or how the body protects itself from excess iron.”

Excess iron is particularly problematic for patients with chronic blood disorders including sickle cell disease (SCD) and thalassemia, which often require regular blood transfusions as treatment. These transfusions are lifesaving but can also cause a life-threatening accumulation of iron in the body.

“Normally, the body produces balanced amounts of repressor protein and activator proteins and mRNA to have just the right amount of ferritin to collect and store and manage the iron in the body’s cells,” said Dr. Theil. “When you start treating patients with transfusions, we are creating iron in concentrations that are way outside the normal range of what the body is used to managing. The existing mechanisms just do not have the range to fully respond to hypertransfusion iron overload.”

Current iron overload treatments rely on chelation therapy to bind excess iron and remove it from the body. Dr. Theil’s study, however, has the potential to provide a vital new complementary tool for the treatment of iron overload.

Researchers have known that the increased synthesis of ferritin observed in cells, animals and people involved a noncoding riboregulator in the ferritin messenger RNA (mRNA) called the iron-responsive element, or IRE, which binds a protein that prevents ferritin synthesis. In the current study, Dr. Theil and her colleagues added Fe2+ in solution to IRE-RNA, which caused conformational changes at two critical protein-binding sites.

“This conformational change effectively pushes off the protein that inhibits ferritin synthesis and pulls on the protein that activates ferritin synthesis. The end result is increased ferritin production,” said Dr. Theil.

Increasing ferritin production in patients with iron overload would increase the body’s ability to manage and the store the iron itself, providing an even longer window before or between the use of chelation therapy.

While further studies are required to develop and test the efficacy of this approach, the study illustrates for the first time the exact mechanism by which iron (Fe2+) increases ferritin production. The study also provides a novel model for controlling viral RNAs or other metabolic mRNAs that use similar strategies.

“Using this model, we could study the mRNA structure of a particular virus in order to develop drugs that would interact with the mRNA and modify the virus’s ability to produce a particular protein; that could stop the virus from reproducing and stop the virus infection,” said Dr. Theil.

At a minimum, the study provides fundamental new knowledge about how iron in particular, but metals in general, interact with mRNA, and opens up whole new avenues of research.

“Understanding the basic principle that we clearly demonstrate here - that mRNA can bind to two different proteins, depending on whether metabolic iron is bound to it – is a whole new approach that needs to be fully exploited and understood,” said Dr. Theil

About Children’s Hospital & Research Center OaklandChildren’s Hospital & Research Center Oakland is Northern California’s only independent not-for-profit regional medical center for children. Children’s Hospital Oakland is a national leader in many pediatric specialties and sub-specialties including hematology/oncology, neonatology, cardiology, orthopedics, sports medicine, and neurosurgery. The hospital is one of only two solely designated California Level 1 pediatric trauma centers with the largest pediatric inpatient critical care unit in the region. Children’s Hospital has 190 licensed beds, 201 hospital-based physicians in 30 specialties, more than 2,700 employees, and an annual operating budget of more than $350 million. Children’s is also a premier teaching hospital with an outstanding pediatric residency program and a number of unique Pediatric subspecialty fellowship programs.

Children’s research program, Children’s Hospital Oakland Research Institute (CHORI), is known internationally for state-of-the-art basic and clinical research and translating it into interventions for treating and preventing human diseases. CHORI has 300 members of its investigative staff, a budget of about $50 million, and is ranked among the nation’s top 10 research centers in National Institutes of Health funding to children’s hospitals. For more information, go to www.childrenshospitaloakland.org and www.chori.org.